The present invention relates to therapeutic agents for life-style related diseases in mammals. More specifically, it relates to CD40 signal blocking agents comprising, as an active ingredient, s-triazolo(1,5-a)pyrimidine derivatives represented by formula (1) or at least one of the pharmaceutically acceptable salts thereof, said blocking agents having at least one of the following effects: a) an effect of blocking the CD40 pathway for monocyte/macrophage activation, b) an effect of suppressing CD40 expression, c) an effect of suppressing IL-6 production, d) an effect of suppressing II-12 production, and e) an effect of suppressing MCP-1 production. It also relates to a method of screening agents that reduce a risk of cardiovascular events.
In recent years, with the westernization of life-styles and the aging of the population, cases of heart diseases, cerebrovascular accidents, hypertension, hyperlipemia and ischemic heart diseases are increasing year by year in Japan. In the face of this trend, the Council on Public Health of the Ministry of Health and Welfare (MHW) submitted a report in December 1996 titled xe2x80x9cOn basic policy in fights against diseases with a focus on life-styles,xe2x80x9d and emphasized the need of introducing the concept of xe2x80x9clife-style related diseasesxe2x80x9d in measures for preventing diseases and improving physical fitness of Japanese people.
At about the same time, it was reported (Yasue et al., Am. J. Cardiol. 83: 1308-1313, 1999) in a large scale clinical study, Japanese Antiplatelets Myocardial Infarction Study 2 (JAMIS2), by the MHW contract research on cardiovascular diseases 6-shi-1 xe2x80x9cA study on the effects of antiplatelet and antithrombotic agents in preventing the recurrence of cardiovascular diseasesxe2x80x9d study group, that a long-term continuous administration of trapidil (300 mg/day), an s-triazolo[1,5-a]pyrimidine derivative, remarkably reduced the recurrence rate of myocardial infarction in patients with acute myocardial infarction (p=0.0810), and unlike an antiplatelet drug aspirin, it significantly (p=0.0039) reduced the incidence of secondary cardiovascular events. This is attracting attention from the viewpoint of preventing and treating the aggravation of life-style related diseases.
However, though the result on trapidil in JAMIS suggested a mechanism of action different from that of aspirin is involved in the suppression of cardiovascular events secondary to life-style related diseases in particular acute myocardial infarction, the mechanisms has yet to be elucidated.
For trapidil, it is known trapidil and its derivative, an s-triazolo[1,5-a]pyrimidine derivative of formula (1), is an antiplatelet agent, and partially acts as a phosphodiesterase inhibitor and a competitive inhibitor of PDGF receptor. For trapidil in particular, various pharmacological effects have been reported. For example, it suppresses the hyperplasia of the tunica interna in rodent models of tunica interna smear (Ohnishi et al., Life Sci. 31: 2595-2602, 1982; Tiell et al., Artery 12: 33-50, 1983, and the like). AR12463, a trapidil derivative, is known to suppress the progress of aorta lesions in rabbit models of arteriosclerosis (Beitz et al., Biomed. Biochim. Acta. 50: 101-107, 1991). It is also reported that trapidil suppresses restenosis after PTCA (Matsuno et al., Thromb. Haemost. 74: 1591-1596, 1995, and the like) Trapidil is also known to suppress the differentiation of cultured cells including blood smooth muscle (SMC) (Matsuno et al., supra; Benelli et al., JOcul. Pharmacol. Ther. 11: 157-166, 1995; Bonisch et al., Mol. Pharmacol. 54: 241-248, 1998, and the like). The differentiation of many of them are induced by PDGF, and their effects are beginning to be recognized as the inhibition of PDGF receptor. Recently, it was found that trapidil inhibits the protein kinase cascade that is induced by PDGF and activated by cancers (Bonisch et al., supra: Hoshiya and Awazu et al., Hypertension 31: 665-671, 1998). Furthermore, the inhibitory activity of TNF-xcex1 sysnthesis was found and the treatment of diseases related to TNF-induced pathological disorders has been reported (Kohyo (National Publication of Translated Version) 11-503434).
The results of JAMIS indicated that mechanisms that cannot be simply explained from the viewpoint of platelet agglutination and/or blood coagulation are involved in the onset of cardiovascular events secondary to acute myocardial infarction. Thus, there is a great need for the elucidation of drug profiles required for drugs suppressing cardiovascular events. The supply of such drug profiles is very important as a profile indispensable for dosage guides as an agent for suppressing cardiovascular events, the choice of the drug to be used in combination, and by extension, as sales promotional activities to medical doctors, or improved drugs to be developed in the future. Furthermore, when the mechanism of action leads to information related to gene expression in the patient, it is also important from the viewpoint of the order made healthcare considered to be a future target.
With regard to suppression of the onset of cardiovascular events, there is a report that demonstrates that the onset of coronary artery diseases can be prevented by cholesterol-lowering therapies, in particular a therapy with HMG-COA reductase inhibitors. It is known, however, that the cholesterol-lowering effect alone is not sufficiently effective for the suppression of events or reducing risks thereof (Progress in Medicine 18(5): 1030-1036, 1998), and thus there is a need for a concept useful for the development of new agents for suppressing cardiovascular events.